Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors

Hina Dalal, Malin Dahlgren, Sergii Gladchuk, Christian Brueffer, Sofia K Gruvberger-Saal, Lao H Saal, Hina Dalal, Malin Dahlgren, Sergii Gladchuk, Christian Brueffer, Sofia K Gruvberger-Saal, Lao H Saal

Abstract

Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = -0.18, p = 2.2e-16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
ESR1 and ESR2 mRNA expression in SCAN-B and TCGA data sets. (A) Scatterplot of ESR1 and ESR2 mRNA expression (log2TPM). ESR1 and ESR2 data points are colored by density using 2D kernel density estimation function from the MASS R package. Adjacent to the scatterplot, histograms are shown indicating the frequency of expression values and color-coded according to ERα clinical status. (B) Expression of ESR1 and ESR2 is shown for the TCGA dataset as in panel A.
Figure 2
Figure 2
ESR2 mRNA by PAM50 molecular subtype in SCAN-B (A) and TCGA (B) cohorts, and by age groups (age at diagnosis) in SCAN-B (C) and TCGA (D).
Figure 3
Figure 3
ESR2 expression and association to overall survival (OS) and relapse-free interval (RFI) in the full SCAN-B cohort (A,B), the endocrine-treated sub-group (C,D) and the chemotherapy-treated subgroup (E,F).
Figure 4
Figure 4
ESR2 expression and association to overall survival (OS) and relapse-free interval (RFI) in the SCAN-B clinical groups. (A,B) Patients with ERα-positive, HER2-negative breast cancer; (C,D) ERα-positive, HER2-positive breast cancer; (E,F) Triple-negative breast cancer (TNBC); and (G,H) ERα-negative, HER2-positive breast cancer.
Figure 5
Figure 5
Multivariate analysis of high ESR2 expression in the full SCAN-B cohort, the endocrine-treated group, and the triple-negative breast cancer (TNBC) group.
Figure 6
Figure 6
Gene Set Enrichment Analysis (GSEA; GO category: Biological Process) of genes ranked by fold change (log2FC) and p-value < 0.05, associated with ESR2-high vs -low in SCAN-B. GSEA analysis based on ESR2-high vs -low was performed separately for the ERα-positive (A) and ERα-negative (B) subgroups. Categories found enriched in both subgroup analyses are indicated by red text.

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